Endogenous adenosine (i.e., naturally occurring adenosine) acts on G protein-coupled receptors (adenosine receptors, ARs) in the central nervous system to suppress seizures and pain, and to blunt the effects of ischemia (a restriction in blood supply to tissues). In addition, adenosine has AR-independent epigenetic effects based on interactions with the transmethylation pathway. There is a dynamic equilibrium between extracellular adenosine levels and its intracellular content that is mediated by either equilibrative (ENTs) or concentrative (CNTs) transporters of nucleosides. Within the brain the concentration of adenosine is largely under the control of metabolic clearance through astrocytic adenosine kinase (AdK), which converts adenosine to 5′-AMP. By inhibiting AdK, the adenosine concentration can be exogenously raised.
It may therefore be possible to target the AR-independent effects of adenosine while avoiding excessive AR activation, by administering brain-penetrant human (h) AdK inhibitors.